A rapid LC-MS/MS method for simultaneous determination of quetiapine and duloxetine in rat plasma and its application to pharmacokinetic interaction study
Xiujuan Chen a,1, Chen Liang b,1, Lijun Cui c, Jian Le d, Zheyuan Qian a, Runsheng Zhang b,**, Zhanying Hong a,*, Yifeng Chai a
a Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai Key Laboratory for Pharmaceutical Metabolites Research, Shanghai 200433, China
b Shanghai Institute of Forensic Science, Shanghai Key Laboratory of Crime Scene Evidence, Shanghai 200083, China
c School of Pharmacy, Shanghai University of Medicine &Health Sciences, Shanghai 201318, China
d Shanghai Institute of Food and Drug Control, Shanghai 201083, China
Combinations of new antidepressants like duloxetine and second-generation antipsychotics like quetiapine are used in clinical treatment of major depressive disorder, as well as in forensic toxicology scenarios. The drugedrug interaction (DDI) between quetiapine and duloxetine is worthy of attention to avoid unnecessary adverse effects. However, no pharmacokinetic DDI studies of quetiapine and duloxetine have been reported. In the present study, a rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of quetiapine and duloxetine in rat plasma. A one-step protein precipitation with acetonitrile was applied for sample preparation. The analytes were eluted on an Eclipse XDB-C18 column using the mixture of acetonitrile and 2 mM ammonium formate containing 0.1% formic acid at a gradient elution within 6.0 min. Quantification was performed in multiple-reactionmonitoring mode with the ion transitions m/z 384.4 → 253.2 for quetiapine, m/z 298.1→154.1 for duloxetine and m/z 376.2→165.2 for IS (haloperidol), respectively. Good linearity was obtained in the range of 0.50-100 ng/mL for quetiapine (r2 = 0.9972) and 1.00-200 ng/mL for duloxetine (r2 = 0.9982) using 50 µL of rat plasma, respectively. The method was fully validated with accuracy, precision, matrix effects, recovery and stability. The validated data have met the acceptance criteria in FDA guideline. The method was applied to a pharmacokinetic interaction study and the results indicated that quetiapine had significant effect on the enhanced plasma exposure of duloxetine in rats under combination use. This study could be readily applied in therapeutic drug monitoring of major depressive disorder patients receiving such drug combinations.
Keywords: LC-MS/MS, Quetiapine, Duloxetine, Pharmacokinetics, Drugedrug interaction